| CTRI Number |
CTRI/2025/02/080989 [Registered on: 20/02/2025] Trial Registered Prospectively |
| Last Modified On: |
18/02/2025 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug |
| Study Design |
Randomized, Parallel Group, Active Controlled Trial |
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Public Title of Study
|
A major study is testing two treatments for esophageal cancer that can still be removed with surgery. One group gets three chemo drugs before surgery, while the other gets the same chemo plus an immune-boosting treatment. The goal is to see which shrinks tumors better and improves patient outcomes |
|
Scientific Title of Study
|
Phase III RCT comparing triplet neoadjuvant chemotherapy with triplet neoadjuvant chemoimmunotherapy in patients with locally advanced resectable esophageal squamous carcinoma |
| Trial Acronym |
NIL |
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| NIL |
NIL |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Dr Nandini Menon |
| Designation |
Associate Professor |
| Affiliation |
Tata Memorial Centre |
| Address |
Tata Memorial Centre Department of Medical Oncology OPD No 204 2nd Floor Dr E Borges Marg Parel
Mumbai
MAHARASHTRA
400012
India |
| Phone |
09769178270 |
| Fax |
|
| Email |
nandini.menon1412@gmail.com |
|
Details of Contact Person
Scientific Query
|
| Name |
Dr Nandini Menon |
| Designation |
Associate Professor |
| Affiliation |
Tata Memorial Centre |
| Address |
Tata Memorial Centre Department of Medical Oncology OPD No 204 2nd Floor Dr E Borges Marg Parel
Mumbai
MAHARASHTRA
400012
India |
| Phone |
09769178270 |
| Fax |
|
| Email |
nandini.menon1412@gmail.com |
|
Details of Contact Person
Public Query
|
| Name |
Dr Nandini Menon |
| Designation |
Associate Professor |
| Affiliation |
Tata Memorial Centre |
| Address |
Tata Memorial Centre Department of Medical Oncology OPD No 204 2nd Floor Dr E Borges Marg Parel
Mumbai
MAHARASHTRA
400012
India |
| Phone |
09769178270 |
| Fax |
|
| Email |
nandini.menon1412@gmail.com |
|
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Source of Monetary or Material Support
|
| Tata Memorial Centre, Dr E Borges Marg Parel Mumbai 400012 |
|
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Primary Sponsor
|
| Name |
Tata Memorial Centre |
| Address |
Tata Memorial Centre Dr E Borges Marg Parel Mumbai 400012 |
| Type of Sponsor |
Research institution and hospital |
|
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Details of Secondary Sponsor
|
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Countries of Recruitment
|
India |
|
Sites of Study
|
| No of Sites = 1 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Nandini Menon |
Tata Memorial Centre |
Tata Memorial Centre Department of Medical Oncology OPD No 204 2nd Floor Dr E Borges Marg Parel
Mumbai
MAHARASHTRA |
09769178270
nandini.menon1412@gmail.com |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 1 |
| Name of Committee |
Approval Status |
| Institutional Ethics Committee - II |
Approved |
|
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Regulatory Clearance Status from DCGI
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Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: C159||Malignant neoplasm of esophagus, unspecified, (2) ICD-10 Condition: C155||Malignant neoplasm of lower thirdof esophagus, (3) ICD-10 Condition: C154||Malignant neoplasm of middle thirdof esophagus, (4) ICD-10 Condition: C158||Malignant neoplasm of overlappingsites of esophagus, (5) ICD-10 Condition: C153||Malignant neoplasm of upper thirdof esophagus, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Intervention |
Docetaxel, Cisplatin/Carboplatin and 5-FU/Capecitabine |
Patients will receive Docetaxel, Cisplatin/Carboplatin and 5-FU/Capecitabine.
5FU will be dosed at 750 mg/m2 continuous intravenous infusion on days 1 to 5. Cisplatin will be dosed at 75 mg/m2on day 1 of each cycle, diluted in 500ml of 0.9% normal saline (with appropriate pre- and post-chemotherapy hydration, and anti-emetic measures).
Carboplatin AUC 5 or 6 (calculated by Calvert formula) will be administered intravenous, in 250-500ml 0.9%NS or dextrose solutions over 30-60mins on Day 1.
Docetaxel will be dosed at 75mg/m2 intravenous on day 1. (500mL sodium chloride 0.9% non-PVC infusion bag with a 0.22 micron in-line filter).
Capecitabine will be dosed at 650mg/m2, twice a day, daily, every 21-days, starting on day 1 of chemotherapy.
Intervention will be from randomization till disease progression or till death |
| Comparator Agent |
Docetaxel, Cisplatin/Carboplatin, 5-FU/Capecitabine, and Nivolumab. |
5FU will be dosed at 750 mg/m2 continuous intravenous infusion on days 1 to 5. Cisplatin will be dosed at 75 mg/m2on day 1 of each cycle, diluted in 500ml of 0.9% normal saline (with appropriate pre- and post-chemotherapy hydration, and anti-emetic measures).
Carboplatin AUC 5 or 6 (calculated by Calvert formula) will be administered intravenous, in 250-500ml 0.9%NS or dextrose solutions over 30-60mins on Day 1.
Docetaxel will be dosed at 75mg/m2 intravenous on day 1. (500mL sodium chloride 0.9% non-PVC infusion bag with a 0.22 micron in-line filter).
Capecitabine will be dosed at 650mg/m2, twice a day, daily, every 21-days, starting on day 1 of chemotherapy
Nivolumab 40 mg would be administered in 100 ml NS over 60 minutes every 3 weekly.
Intervention will be from randomization till disease progression or till death |
|
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Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
99.00 Year(s) |
| Gender |
Both |
| Details |
Subjects must have histologically proven squamous cell carcinoma of the esophagus or esophagogastric junction.
Tumor should be surgically resectable. Pre-treatment stage cT2-4a, N0-3, M0. Cervical esophageal cancers should be resectable without the need for laryngectomy.
Male, female, or transgender subjects aged 18 to 75 years.
Eastern Cooperative Oncology Group ECOG performance status 0 to 2.
Subjects must have normal organ and marrow function as defined below:
a. Hematologic: Absolute neutrophil count ANC greater than or equal to 1.0x109 per liter, platelet count greater than or equal to 100x109 per liter, and hemoglobin greater than or equal to 8 grams per deciliter.
b. Hepatic: Total bilirubin level less than or equal to 1.5 times the upper limit of normal ULN range and AST and ALT levels less than or equal to 2.5 times ULN.
c. Renal: Estimated creatinine clearance greater than or equal to 30 milliliters per minute.
d. Pulmonary: Patients should have adequate pulmonary function tests.
Patients with HIV are potentially eligible, as long as they have a CD4 count greater than 200, are on concurrent HAART highly active antiretroviral therapy, and absence of active AIDS-defining conditions.
Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing potential.
Women of childbearing potential must be willing to consent to using effective contraception such as hormonal contraceptives, bilateral tubal ligation, barrier with spermicide, intrauterine device while on treatment and for at least 3 months thereafter. A man who is the partner of a woman of childbearing potential must be willing to consent to using effective contraception such as vasectomy or barrier with spermicide while on treatment and for 3 months thereafter.
Both men and women of all races and ethnic groups are eligible for this study.
Ability to understand and the willingness to sign a written informed consent document. |
|
| ExclusionCriteria |
| Details |
1 Subjects who are receiving any other concurrent investigational agents
2 Clinical or radiologic evidence of metastatic disease
3 Patients unfit for curative surgery for any reason
4 Infections Active infection requiring systemic therapy
5 Hepatitis Hepatitis B virus or hepatitis C virus infection at screening. Positive HBV surface antigen with raised HBV DNA or anti HCV antibody screening test positive with raised HCV RNA. Mere presence of HBV or HCV at screening test wont rule the patient out
6 Hypersensitivity to study drug Known prior severe hypersensitivity to investigational product or any component in its formulations
7 Cardiovascular disease Clinically significant active cardiovascular disease unstable angina congestive heart failure Class 2 or more serious uncontrolled cardiac arrhythmia or asymptomatic individuals with ejection fraction below 50 percent
8 Other severe acute or chronic medical conditions including inflammatory bowel disease pneumonitis chronic kidney disease known peripheral neuropathy grade 1 or more chronic liver disease pulmonary fibrosis or psychiatric conditions including recent within the past year or active suicidal ideation or behavior
9 Pregnant women are excluded from this study. Advise females of reproductive potential to use effective contraception during treatment and for at least one month after treatment completion
10 Any other malignancies within the last 5 years other than curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix
11 Immunosuppressants Current use of immunosuppressive medication except for the following intranasal inhaled topical steroids or local steroid injection systemic corticosteroids at physiologic doses of 10 mg per day of prednisone or equivalent steroids as premedication for hypersensitivity reactions steroids for raised intracranial pressure due to the disease itself
12 Autoimmune disease Active autoimmune disease that might deteriorate when receiving a chemotherapeutic agent. Patients with diabetes type 1 vitiligo psoriasis or hypo or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
13 Organ transplantation Prior organ transplantation including allogeneic stem cell transplantation
14 Vaccination Vaccination within 4 weeks of the first dose of Nivolumab and while on study is prohibited except for administration of inactivated vaccines
15 Lactating females There is no information regarding the presence of Nivolumab in human milk the effects on the breastfed infant or the effects on milk production. Since many drugs are excreted in human milk it is advised that a lactating woman should not breastfeed during treatment and for at least one month after the last dose of Nivolumab due to the potential for serious adverse reactions in breastfed infants
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Method of Generating Random Sequence
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Computer generated randomization |
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Method of Concealment
|
Centralized |
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Blinding/Masking
|
Open Label |
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Primary Outcome
|
| Outcome |
TimePoints |
| 3-year event-free survival (EFS) rates |
EFS will be measured from randomization to progression treatment discontinuation or death. It will be evaluated at 1, 2, 3, 4, and 5 years Outcome assessments for both arms: baseline Cycle 2 Day 1 of neoadjuvant chemotherapy (+/-15 days) first follow-up post-chemotherapy (+/-15 days) first follow-up post-surgery (+/-15 days), and at 2 and 4 months post-surgery (+/-15 days) |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
Overall survival OS
Objective Response Rates ORR
Toxicity assessment
Quality of life QOL assessment
R0 Resection rates Peri and post operative complication rates
Pathological response rates Tumour regression grades
Patterns of treatment failure local vs loco regional vs distant
Factors that impact OS Age Gender ECOG PS baseline body weight baseline haemoglobin baseline albumin histopathological grade Axial Imaging or Endoscopy defined location of the primary in the esophagus presence or absence of dysphagia pre operative T stage T2 vs T3 4 and N stage N0 1 vs N2 3 Neoadjuvant chemotherapy regimen used treatment completion rates response to neoadjuvant therapy underwent surgery versus not receipt of adjuvant immunotherapy versus not
Factors that impact EFS Same as factors affecting OS |
Overall Survival OS
Measured from the date of randomization until death from any cause. It will be described as median OS and as survival rates at 1 2 3 4 and 5 years post randomization
Objective Response Rates ORR
Calculated as the percentage of patients achieving a complete or partial response based on RECIST version 1.1 assessed after completion of neoadjuvant therapy
Toxicity Assessment
Acute Toxicity Assessed from the day of randomization until 90 days after the start of chemoradiotherapy CRT
Chronic Toxicity Evaluated for events occurring beyond 90 days from the start of CRT
Quality of Life QOL Assessment
Conducted using EORTC QLQ C30 and QLQ OES18 questionnaires at
Baseline
Cycle 2 Day 1 of neoadjuvant therapy 15 days
First follow up post treatment 15 days
First follow up post surgery 15 days
2 months post surgery 15 days
4 months post surgery 15 days
R0 Resection Rates
Assessed at the time of surgery. Resection is considered R0 if no tumor cells are found within 1 mm of any resection margin
Peri and Post Operative Complication Rates
Evaluated at 30 days and 90 days post surgery using the Clavien Dindo classification
Pathological Response Rates and Tumor Regression Grades TRG
Determined after surgery during the pathological evaluation of the resected specimen
Patterns of Treatment Failure Local Loco Regional Distant
Monitored during follow up visits as part of disease recurrence surveillance
Factors Impacting OS and EFS
Evaluated throughout the study with data collected during follow up at regular intervals up to 5 years post randomization |
Exploratory outcomes Biomarker analysis
|
Biomarker analysis will be conducted as part of exploratory objectives, with specific timepoints depending on sample availability and study milestones. |
|
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Target Sample Size
|
Total Sample Size="362"
Sample Size from India="362"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 3 |
|
Date of First Enrollment (India)
|
01/03/2025 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="9"
Months="0"
Days="0" |
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Recruitment Status of Trial (Global)
|
Not Applicable |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
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Publication Details
|
N/A |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
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Brief Summary
|
Esophageal cancer, which affects the food pipe,
is common in India, with nearly 10% of all new cancer cases each year being
this type. The most frequent type of esophageal cancer is called squamous cell
carcinoma. When diagnosed early enough, patients with this type of cancer can
undergo surgery to remove the tumor, but they often receive chemotherapy before
surgery to shrink the tumor and improve the chances of a successful surgery.
However, even with this approach, the cancer returns in about 40% of patients
within three years.
To reduce the chances of cancer coming
back, this study will explore whether adding a low dose of immunotherapy (a
treatment that helps the body’s immune system fight cancer) to the usual
chemotherapy before surgery can improve outcomes. Immunotherapy has been shown
to be helpful in other trials, but it is usually expensive. In this study, a
more affordable low-dose version of immunotherapy called Nivolumab will be used
alongside chemotherapy.
The study will compare two groups of
patients with advanced but still operable esophageal squamous cell cancer. One
group will receive the standard chemotherapy treatment, and the other will
receive chemotherapy plus the low-dose immunotherapy. The main goal is to see
if the combination treatment helps patients live longer without their cancer
returning (event-free survival) over a period of three years. Study will also
look at overall survival, how well the treatments shrink the tumor, the success
rate of surgeries, and the patients’ quality of life.
Aim:To evaluate if triplet neoadjuvant
chemotherapy with low-dose immunotherapy prolongs event-free survival compared
to triplet neoadjuvant chemotherapy alone in patients with locally advanced
resectable esophageal squamous carcinoma
Primary Objective: 3-year event-free survival (EFS)
Secondary Objectives: Overall Survival
(OS), Objective Response Rate (ORR), R0 resection rates, pathological
responses, patterns of treatment failure, Quality of Life (QOL), Safety,
factors that impact OS and EFS.
Tertiary Objectives: Exploring biomarkers
Study Design:Randomized controlled, open-label, phase III study, superiority design
Study Population: Eligible patients with locally
advanced resectable esophageal squamous carcinoma planned for curative intent
treatment
Sample Size:362
Treatment Plan:Eligible patients will be randomized
in a 1:1 fashion to triplet neoadjuvant chemotherapy (Docetaxel,
Cisplatin/Carboplatin, 5-FU/Capecitabine) or neoadjuvant chemoimmunotherapy
(Docetaxel, Cisplatin/Carboplatin, 5-FU/Capecitabine with Nivolumab 40mg). Response
assessment will be done after completion of neoadjuvant treatment followed by
assessment for surgery. Adjuvant treatment (chemotherapy, immunotherapy, or
radiotherapy) will be as per discussion in the thoracic disease management
group. Patients will be assessed with CT scans every 2-3 months in the first 2
years, every 6 months for the next 3 years, and thereafter yearly for
assessment of disease recurrence. Following progression/discontinuation,
patients will be followed up and treated as per standard institutional policy.
Patients will be followed every 2-3 months until death for survival analysis.
Duration of Study:9 years (6 years
of accrual and 3 years of follow up)
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